In the present application, two hypotheses concerning the immune mechanisms that protect mice against vaginal infection by virus will be tested. Hypothesis 1: Specific antibodies of the IgA and IgG isotypes in the vaginal lumen contribute to immunity to HSV-2. Aim 1 is to characterize and measure the concentrations of IgA and IgG antibodies in the vaginal lumen of normal and immune mice by immunoblotting and ELISA. Aim 2 is to demonstrate that antibodies extracted from vaginal mucus of immune mice can neutralize HSV-2 at their concentrations in situ. Aim 3 is to clarify the role of secretory IgA in vaginal immunity using IgA knockout mice. Aim 4 is to determine whether vaginal immunization with attenuated HSV-2 causes long-term recruitment of IgG plasma cells to the vagina, local production of IgG, and increased specific IgG titers in vaginal secretions relative to parenteral immunization. Hypothesis 2: Recirculating memory lymphocytes in the vagina contribute to immunity to HSV-2; upon stimulation by challenge virus in the vagina, these cells release interferons that inhibit virus replication in the epithelium. Aim 5 is to demonstrate and characterize lymphoid cell migration from the vaginal epithelium to the draining iliac lymph nodes. Aim 6 is to demonstrate that T lymphocytes play a role in immunity to vaginal infection using in vivo depletion of T lymphocyte subsets. Aim 7 is to measure the concentrations of interferons and tumor necrosis factor-alpha in vaginal mucus and demonstrate that they play a role in immunity to vaginal infection by depletion in vivo.